The present invention relates to a process for making bicalutamide and/or its intermediates using a sulfinic acid salt and to certain intermediate compounds useful in the production of bicalutamide.
Bicalutamide is the common name for the compound 4-cyano-3-trifluoromethyl-N-(3-p-fluorophenylsulfonyl-2-hydroxy-2-methylpropionyl)aniline, and is represented by the formula (1):

Bicalutamide is a non-steroidal antiandrogen pharmaceutically active agent that is generally used in the treatment of prostate cancer; i.e., for androgen deprivation treatment, although other androgen dependent conditions may also be treated. Bicalutamide is commercially available in a pharmaceutical composition as a racemate under the brand name CASODEX® (Astra-Zeneca). The R-stereoisomer of bicalutamide has been proposed in U.S. Pat. No. 5,985,868 as being more beneficial than the racemate.
U.S. Pat. No. 4,636,505 teaches a genus of acylanilides including bicalutamide as having antiandrogen activity. Three processes are generically put forth for making the various acylanilides. The first process comprises reacting an acid of the formula HO2C—CR5R6-A1-X1-A2-R7 or a reactive derivative thereof with an aniline compound of a specified formula. The substituents R5 and R6 include hydroxyl and methyl groups; Al includes methyl, ethyl and ethylidene; X1 includes oxygen, sulfur, sulfinyl, sulfonyl, imino, and methylimino; A2 can be a direct link; and R7 includes substituted phenyl. This process is not exemplified in making bicalutamide in the U.S. Pat. No. 4,636,505 patent. Instead, the examples only show this process for making thio or oxy derivatives wherein X1 is sulfur or oxygen. However, the sulfur is taught to be oxidized to sulfinyl or sulfonyl and thus bicalutamide can be produced with subsequent oxidation by this general reaction according to the following reaction scheme:
wherein the thio derivative (C) is then oxidized to produce bicalutamide (i.e., sulfur (S) becomes sulfonyl (SO2)). The starting compound (A) having X as a methoxy group was prepared by opening the epoxy-ring of methyl 2,3-epoxy-2-methylpropionate (D) by reacting the same with p-fluorothiophenol (E) as represented below:

The second process likewise uses a thiophenol compound in order to make a thio analogue of bicalutamide. The process condenses an appropriate thiophenol such as p-fluorothiophenol (E) with an appropriate epoxy-anilide such as (F) to make a thio-analogue of, inter alia, bicalutamide (C). Again, the thio analogue must be oxidized to obtain a sulfonyl linking group in order to make bicalutamide.

The starting epoxy-anilide (F) was prepared by condensation of the aniline (B) with methacryloylchloride and epoxidation of the so obtained acryl-anilide (G)

U.S. Pat. No. 4,636,505 also suggests that the compound (F) may be replaced in this process by an activated hydroxy-compound (H) wherein L is a leaving group:
However, no working example of a process employing a compound of a general formula (H) was provided in the U.S. Pat. No. 4,636,505.
The third process disclosed in U.S. Pat. No. 4,636,505 comprises reacting an organometallic compound of the formula R7-A2-X1-A1-M, where M is a metal radical, with an appropriate aniline derivative such as:
to form the corresponding acylanilide. No example of this process is set forth in the U.S. Pat. No. 4,636,505 patent.
Consistent with the examples, U.S. Pat. No. 4,636,505 teaches that when X1 is desired to be sulfinyl or sulfonyl, the compound may be prepared by oxidizing the corresponding thio-acylanilide compound. Based on these teachings and examples, U.S. Pat. No. 4,636,505 can be seen as teaching the use of a thiophenol of compound (E) above to make bicalutamide by first forming the thio-acylanilide analogue compound (C) followed by oxidation to bicalutamide. The thiophenol can be reacted to form the hydroxy acid of compound (A) which is then subsequently reacted with an aniline compound, or, the thiophenol can be reacted with an acylanilide compound (F) to form the thio bicalutamide analogue.
Other synthetic routes have been proposed for making bicalutamide, especially optically pure bicalutamide. In J. Med. Chem. 885–887 (1988) and J. Med. Chem. 31, 954 (1988) a starting compound of the above compound (H) wherein L is Br in rigid conformation was prepared by bromination of N-methacrylamide of natural (S)-proline (by asymmetric bromolactonisation according to Terashima) to form the cyclic compound (L)
which was hydrolyzed to yield the (S)-isomer of 2-hydroxy-3-bromoisobutyric acid (N).
This was coupled with the aniline (B) to yield the substituted bromohydrine (H) (L=Br) which, after reaction with p-fluorothiophenol (E), provided for thio-bicalutamide (C), however with undesired (S) conformation.
In U.S. Pat. No. 6,019,957, the similar synthesis of (R)-bicalutamide via a iodinated analogue of (H) (i.e. with L=I) was described, starting with (R)-proline. The R-proline provides for the desired conformation. However, it is the unnatural proline isomer and thus highly expensive.
WO01/00608 discloses another route for making racemic or optically pure bicalutamide and also provides a summary of the above processes. In this document, the three routes from U.S. Pat. No. 4,636,505 are set forth for making bicalutamide in FIGS. 1–3 thereof. Another route based on the cyclized N-methacrylamide of proline is shown in FIG. 4 of WO01/00608. The fifth and purportedly inventive route forms a compound (H) where L is —OSO2—R via an amidation reaction of the aniline (B) with a cyclic sulfite-ester of 2,3-dihydroxyisobutyric acid chloride (M)
The reaction can produce racemic or optically pure bicalutamide depending on the optical purity of the starting 2,3-dihydroxy-2-methyl-propionic acid used to make the cyclic sulfite-ester (M). According to FIG. 5 of WO01/00608 the compound (H) is reacted with the sodium salt of p-fluorothiophenol to make the thio analogue of bicalutamide (C) followed by oxidation thereof to produce bicalutamide.
WO 01-28990 also describes several methods for how to obtain bicalutamide, optionally via a stereoselective synthesis of the compound (A). The processes include the use of an oxiran ring as in U.S. Pat. No. 4,636,505, a cyclized proline derivative similar to the above articles, or citramalic acid. The later process starts from natural S-citramalic acid which is firstly protected by bromal and brominated upon decarboxylation to form a compound (K).
This compound is condensed with p-fluorothiophenol (E) with subsequent hydrolysis of the protective group, resulting in a compound (A), which is then amidated with the aniline (B) and the formed compound (C) finally oxidized to produce bicalutamide.
The fully elucidated processes for making bicalutamide in the above-mentioned documents all use a p-fluorothiophenol compound, albeit with different reaction partners, to provide a thio linkage which is oxidized in a final step to form the sulfonyl linkage required for bicalutamide. But p-fluorothiophenol is a toxic and unpleasant smelling compound making it somewhat difficult to work with, especially on a large scale.